Isocitrate dehydrogenase (IDH) catalyzes oxidative decarboxylation of isocitrate to 2-oxoglutarate (alpha-ketoglutarate) while producing carbon dioxide and NADPH/NADH. This process plays an important role in the metabolism of cells. Depending on electron acceptors, these enzymes can be divided into two distinct subclasses, one using NAD(+) and the other using NADP(+). In five reported isocitrate dehydrogenases, three of them are NAD(+)-dependent isocitrate dehydrogenases, and mainly present in mitochondrial matrix; the other two are NADP(+)-dependent, i.e. isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2. Isocitrate dehydrogenase 1 is mainly present in the cytoplasm, while isocitrate dehydrogenase 2 is mainly present in the mitochondria. Mutations of isocitrate dehydrogenase occur in a wide variety of cancer types including (but not limited to) glioma, glioblastoma, paraganglion cell tumors, acute leukemia, prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T cell leukemia, melanoma, etc. (see L. Deng, et al., Trends Mol. Med., 2010, 16,387; T. shibata et al., Am. J. Pathol., 2011, 178(3), 1395; Gaal et al., J. Clin. Endocrinol. Metab. 2010; Hayden et al., Cell cycle, 2009; Balss et al., Acta Neuropathol., 2008).
Non-mutated IDH1 catalyzes oxidative decarboxylation of isocitrate to alpha-ketoglutarate, thereby reducing NAD+(NADP+) to NADP (NADPH) in the following forward reactions:Isocitrate+NAD+(NADP+)→α-ketoglutarate+CO2+NADH (NADPH).
The mutant isocitrate dehydrogenase loses the above normal function, but instead catalyzes NAPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate (2HG). The concentration level of 2HG in normal cells is very low. The production of high concentration of 2HG contributes to the formation and development of cancer (Dang, L et al, Nature 2009, 462: 739-44). For example, a high concentration of 2-HG was detected in patients of acute leukemia with IDH mutation. (S. Gross et al., J. Exp. Med., 2010, 207(2), 339). High concentration of 2HG is highly correlated with oncogenes. Therefore, there is an urgent need in the art to develop mutant IDH inhibitors.